Neuroendocrine Neoplasms of the Female Genitourinary Tract: A Comprehensive Overview

Simple Summary Primary neuroendocrine neoplasms (NENs) are a rare, heterogeneous group of tumors that include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinoma, and paraganglioma. NENs in the urinary tract are observed in <0.05% of individuals, in whom the bladder is the most common site. In this review, we described the epidemiology, pathogenesis, imaging, staging, and management of the genitourinary NENs. Abstract Primary neuroendocrine neoplasms are a rare heterogeneous group of tumors that include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinoma, and paraganglioma. An extensive literature search was used to compile the data regarding epidemiology, pathogenesis, imaging features, and management of the urinary system NENs. We also included the updated staging of the NENs at various locations of the urinary system.


Introduction
Neuroendocrine neoplasms (NENs) are a diverse group of tumors arising from neuroendocrine cells and share similar features throughout the body. NENs in the urinary tract are observed in <0.05% of individuals, in whom the bladder is the most common site ( Figure 1) [1]. The free radical and genetic damage secondary to smoking are the most important risk factors for urothelial carcinoma and urinary tract NENs [2]. This manuscript discusses the epidemiology, pathogenesis, imaging, and management of NENs in the kidney, ureter, bladder, and urethra.

Epidemiology, Presentation, and Pathogenesis
Primary renal NENs are rare neoplasms with around 100 cases reported in the literature, as per our knowledge ( Figure 2) [3]. The 2016 WHO classification of renal tumors classified renal neuroendocrine neoplasms into well-differentiated NET, small-cell NEC, and large-cell NEC (Table 1) [4]. Renal carcinoid tumors, also known as well-differentiated NET of the kidneys, are rare, slow-growing neoplasms. They were first described by Resnick et al. in 1966 [5,6]. In a study by Hansel et al., the median age of presentation for renal NEN is 52 years, and the tumor equally affected male and female patients [7]. Primary renal carcinoid is the second most common genitourinary carcinoid tumor after testicular/ovarian carcinoids [8]. It is asymptomatic and incidentally detected in 25-30% of patients [6,9]. Typical symptoms of the carcinoid syndrome, including flushing, edema, and diarrhea, are uncommon and are seen in <10-15% of patients [5,[10][11][12]. The incidence of small-cell renal NEC is rare; approximately 50 cases have been reported in the literature [13][14][15][16][17]. Most of the patients present at the age of 59 years with non-specific symptoms, such as hematuria, weight loss, and abdominal pain. There is no gender predilection, and the right kidney is more commonly involved than the left, with a ratio of 1.5:1 [13]. Evaluation with biochemical tests such as urinary-HIAA and serum chromogranin A and imaging is recommended to assess suspected NENs [18]. Death is seen in around 75% of patients within a year of diagnosis. Primary renal large cell NEC is an extremely rare malignancy; fewer than 10 cases have been reported in the literature [14,[19][20][21][22][23][24]. Renal paragangliomas are rare, and to date, very few cases have been reported in the literature [25].

Epidemiology, Presentation, and Pathogenesis
Primary renal NENs are rare neoplasms with around 100 cases reported in the literature, as per our knowledge ( Figure 2) [3]. The 2016 WHO classification of renal tumors classified renal neuroendocrine neoplasms into well-differentiated NET, small-cell NEC, and large-cell NEC (Table 1) [4]. Renal carcinoid tumors, also known as well-differentiated NET of the kidneys, are rare, slow-growing neoplasms. They were first described by Resnick et al. in 1966 [5,6]. In a study by Hansel et al., the median age of presentation for renal NENs is 52 years, and the tumor equally affected male and female patients [7]. Primary renal carcinoid is the second most common genitourinary carcinoid tumor after testicular/ovarian carcinoids [8]. It is asymptomatic and incidentally detected in 25-30% of patients [6,9]. Typical symptoms of the carcinoid syndrome, including flushing, edema, and diarrhea, are uncommon and are seen in <10-15% of patients [5,[10][11][12]. The incidence of small-cell renal NEC is rare; approximately 50 cases have been reported in the literature [13][14][15][16][17]. Most of the patients present at the age of 59 years with non-specific symptoms, such as hematuria, weight loss, and abdominal pain. There is no gender predilection, and the right kidney is more commonly involved than the left, with a ratio of 1.5:1 [13]. Evaluation with biochemical tests such as urinary-HIAA and serum chromogranin A and imaging is recommended to assess suspected NENs [18]. Death is seen in around 75% of patients within a year of diagnosis. Primary renal large cell NEC is an extremely rare malignancy; fewer than 10 cases have been reported in the literature [14,[19][20][21][22][23][24]. Renal paragangliomas are rare, and to date, very few cases have been reported in the literature [25].

Epidemiology, Presentation, and Pathogenesis
Primary renal NENs are rare neoplasms with around 100 cases reported in the literature, as per our knowledge ( Figure 2) [3]. The 2016 WHO classification of renal tumors classified renal neuroendocrine neoplasms into well-differentiated NET, small-cell NEC, and large-cell NEC (Table 1) [4]. Renal carcinoid tumors, also known as well-differentiated NET of the kidneys, are rare, slow-growing neoplasms. They were first described by Resnick et al. in 1966 [5,6]. In a study by Hansel et al., the median age of presentation for renal NEN is 52 years, and the tumor equally affected male and female patients [7]. Primary renal carcinoid is the second most common genitourinary carcinoid tumor after testicular/ovarian carcinoids [8]. It is asymptomatic and incidentally detected in 25-30% of patients [6,9]. Typical symptoms of the carcinoid syndrome, including flushing, edema, and diarrhea, are uncommon and are seen in <10-15% of patients [5,[10][11][12]. The incidence of small-cell renal NEC is rare; approximately 50 cases have been reported in the literature [13][14][15][16][17]. Most of the patients present at the age of 59 years with non-specific symptoms, such as hematuria, weight loss, and abdominal pain. There is no gender predilection, and the right kidney is more commonly involved than the left, with a ratio of 1.5:1 [13]. Evaluation with biochemical tests such as urinary-HIAA and serum chromogranin A and imaging is recommended to assess suspected NENs [18]. Death is seen in around 75% of patients within a year of diagnosis. Primary renal large cell NEC is an extremely rare malignancy; fewer than 10 cases have been reported in the literature [14,[19][20][21][22][23][24]. Renal paragangliomas are rare, and to date, very few cases have been reported in the literature [25].

Pathogenesis
There are many hypotheses explaining the cellular origins of neuroendocrine neoplasms in the kidneys: tumors (i) arise from renal stem cells that progress towards neuroendocrine lineage [18] or (ii) arise from entrapped neural crest cells in the kidney during embryogenesis [33] or (iii) develop alongside congenital abnormalities of the kidney [18] or (iv) are secondary to the metaplasia of pyelocaliceal urothelium resulting from chronic inflammation [26]. Renal NENs arises most commonly in individuals with congenital or acquired renal anomalies, such as horseshoe kidney (26% of renal NENs), polycystic disease, and mature cystic teratoma (15% of renal NENs) [34][35][36][37][38]. Krishnan et al. speculated that renal NENs arises from the already existing hyperplasia of neuroendocrine cells in the metastatic or teratomatous epithelium of the horseshoe kidney [34]. Primary renal smallcell NEC is a poorly differentiated tumor with a poor prognosis that is similar to small-cell NEC at other sites. Unlike renal parenchymal small-cell NEC, the ones arising from the renal pelvis are associated with urothelial or squamous cell carcinoma [17,39,40]. The origin of renal small-cell NEC is different from that of clear cell renal cell carcinoma. The pattern of chromosomal aberration can explain this. Gain of multiple chromosomes, loss of p53, and amplification of MYC are seen in small-cell renal NEC, whereas loss of the short arm of chromosome 3 (3p) is observed in clear cell renal cell carcinoma [28]. However, El-Naggar reported a loss of heterozygosity in chromosome 3p21 and suggested that this event is preliminary to all the renal neoplasms [41]. Renal paragangliomas are usually benign, and around 10% of patients encounter malignant transformation [29]. Classic cancer predisposition syndromes, including von Hippel-Lindau, multiple endocrine neoplasia type-2, and neurofibromatosis type 1 disease are associated with paragangliomas. Metastases are rare in VHL and MEN2 associated paragangliomas, whereas they may occur in 12% of NF-1 associated diseases [42]. The risk of metastases is high in succinate dehydrogenase subunits B (25-50%) and A (12%) [43].

Imaging
Ultrasound of renal NENs shows an iso-to hyperechoic mass with a peripheral anechoic or hypoechoic rim [11,12,44]. Computed tomography demonstrates a well-circumscribed solid, hypodense tumor with minimal enhancement in contrastenhanced venous phase CT that corresponds to hypo-or avascular lesions on angiography (   [18,45]. Heterogeneity and calcifications on CT can be seen in 60% and 26% of cases [9,33]. Around 75% of patients present with tumors > 4 cm, and >50% of patients demonstrate extrarenal invasion (perinephric, renal vein, or renal sinus fat) or distant spread of tumor [12,46]. However, differentiation is challenging, solely based on CT or MR imaging findings among renal NENs and renal cell carcinoma ( Table 2). In addition, smaller carcinoids are difficult to visualize on conventional imaging. Octreotide scintigraphy complements CT or MRI and aids in diagnostic evaluation, staging, and follow-up of tumors and metastases with high sensitivity (85%) [13,47]. However, the major limitation is the uptake of tracer material by the normal renal parenchyma, obscuring the suspicious lesion. Heterogeneous signal intensity on T1 and T2WI with areas of high signal intensity on T1WI due to hemorrhage; The mass enhances with contrast administration extrarenal invasion (perinephric, renal vein, or renal sinus fat) or distant spread of tumor [12,46]. However, differentiation is challenging, solely based on CT or MR imaging findings among renal NEN and renal cell carcinoma ( Table 2). In addition, smaller carcinoids are difficult to visualize on conventional imaging. Octreotide scintigraphy complements CT or MRI and aids in diagnostic evaluation, staging, and follow-up of tumors and metastases with high sensitivity (85%) [13,47]. However, the major limitation is the uptake of tracer material by the normal renal parenchyma, obscuring the suspicious lesion.

Clear Cell carcinoma
Heterogeneous mass due to necrotic, cystic and hemorrhagic areas; Strong contrast enhancement in corticomedullary and contrast wash out during nephrographic phases Hyper vascular lesion; Hyperintense on T2WI and hypo-to isointense on T1WI; Heterogeneous avid enhancement than the rest of RCC types on contrast administration; Microscopic fat in 60% of cases; CSI: >25% signal loss on opposed phase relative to in-phase imaging due to fat content; Tumor pseudo capsule: hypointense rim on T1WI and T2WI. Renal paragangliomas are more common in the kidney's upper pole, and all patients shall have a biochemical evaluation before surgical resection [49]. Patients with hereditary syndrome-associated paragangliomas are more likely to develop multifocal primary tumors with varying degrees of metastases [50]. Paragangliomas are well-defined tumors with hemorrhagic and necrotic areas on CT, and calcification in 15% of cases [51]. On contrast administration, they exhibit intense homogeneous enhancement secondary to the tumor hypervascularity [51]. Since the MR resolution of tumors is better than that of CT, MR imaging has higher sensitivity in detecting liver metastases and blood vessel invasion [52]. In MR imaging, paragangliomas demonstrate low to intermediate signal intensity on T1-weighted, signal voids on T1-weighted spin-echo, and high signal intensity on T2-weighted imaging sequences [51]. Functional imaging, iodine 123 metaiodobenzylguanidine (I 123 -MIBG), is widely used to identify metastases and differentiate functional from nonfunctional paragangliomas. I 123 -MIBG has high specificity (95-100%) but a low detection rate; the sensitivity ranges from 56 to 72% [53][54][55][56]. The application of PET/CT with 68Ga-DOTA peptides and 18F-fluorodeoxyglucose has increased recently. PET/CT imaging with 68Ga-labeled somatostatin analogs such as DOTATOC, DOTATATE, and DOTANOC is being employed, and it targets the over-expressive somatostatin receptor subtype 2 in the paragangliomas [57]. DOTATATE PET/CT is the better imaging modality in patients with well-differentiated renal NENs. 18F-FDG PET/CT is superior to the 68Ga-based PET/CT, 123I-MIBG, CT, or MRI for high-grade NEC and detects the metastatic or recurrent tumors. It exhibits increased 18F-FDG uptake in SDH and VHL-related tumors and decreased uptake in MEN-2-related tumors. In addition, fluorine-18-labeled dihydroxyphenylalanine, a new tracer, was found to acquire images within hours; compare that to a day for an MIBG scan. The main limitation of FDG-PET is that its specificity is lower than that of 123I-MIBG and 111-In Octreoscan [58,59].
The diagnosis of NENs is based on histopathological and immunohistochemical characteristics of the tumor ( Figure 6). Grossly, the renal NENs is solitary with welldelineated borders from the surrounding normal parenchyma and demonstrates solid (74% of cases) and cystic (49% of cases) surfaces, alongside focal calcification (30% of cases) and the occasional pseudo-capsule [47]. Usually, as the retroperitoneal space is highly distensible, the patients manifest with large tumor masses at diagnosis [33]. In their study, Hansel et al. described the average tumor size being from 2.6 to 17 cm. They reported that around 62% of patients demonstrated metastasis in regional lymph nodes or distant organs [3,7]. Hence, it can be said that the metastases are directly related to the tumor size in the renal NENs [3,60]. Hence, it can be said that the metastases are directly related to the tumor size in the renal NEN [3,60].

Prognosis and Management
Renal NENs have higher survival rates than poorly differentiated renal NENs [3]. Age > 40 years, tumor size > 4 cm, extrarenal tumor invasion, purely solid surface, and >1 mitoses per HPF are the poor prognostic factors in patients with renal NEN [9,10,61]. In the presence of horseshoe kidneys, the carcinoids manifest indolent behavior [12,33,62]. Zhenglin et al. reported regional or distant metastases in 83% and a median overall survival of only 27 months in patients with renal NEC [3]. Patients with renal paraganglioma and metastases at diagnosis have 5-year survival rates ranging from 50 to 70% [30].
Surgery is the mainstay of treatment in renal NENs. The staging of renal NENs is described in Tables 3 and 4. The standard treatment for localized primary renal NENs is nephrectomy with a lymph node dissection ( Figure 7) [18]. As the surgery could be a prognostic factor, radical or partial nephrectomy is the treatment choice for localized or metastatic renal NEN [33]. Resection of the entire visible tumor is recommended in localized renal NEC. Rosenberg et al. described that, as carcinoids tend to be benign, partial nephrectomy or cryoablation of the tumor shall be the standard treatment; therefore, functional nephrons can be spared [63]. Chemotherapy and radiation have no proven benefit in managing NEN in general [13]. When indicated, open surgical resection shall be considered in the case of primary paraganglioma. Cytotoxic chemotherapy is recommended as the first-line therapy in patients with a high tumor burden (extensive metastases),

Prognosis and Management
Renal NENs have higher survival rates than poorly differentiated renal NENs [3]. Age > 40 years, tumor size > 4 cm, extrarenal tumor invasion, purely solid surface, and >1 mitoses per HPF are the poor prognostic factors in patients with renal NENs [9,10,61]. In the presence of horseshoe kidneys, the carcinoids manifest indolent behavior [12,33,62]. Zhenglin et al. reported regional or distant metastases in 83% and a median overall survival of only 27 months in patients with renal NEC [3]. Patients with renal paraganglioma and metastases at diagnosis have 5-year survival rates ranging from 50 to 70% [30].
Surgery is the mainstay of treatment in renal NENs. The staging of renal NENs is described in Tables 3 and 4. The standard treatment for localized primary renal NENs is nephrectomy with a lymph node dissection ( Figure 7) [18]. As the surgery could be a prognostic factor, radical or partial nephrectomy is the treatment choice for localized or metastatic renal NENs [33]. Resection of the entire visible tumor is recommended in localized renal NEC. Rosenberg et al. described that, as carcinoids tend to be benign, partial nephrectomy or cryoablation of the tumor shall be the standard treatment; therefore, functional nephrons can be spared [63]. Chemotherapy and radiation have no proven benefit in managing NENs in general [13]. When indicated, open surgical resection shall be considered in the case of primary paraganglioma. Cytotoxic chemotherapy is recommended as the first-line therapy in patients with a high tumor burden (extensive metastases), symptoms, or rapid progression. Clinically used chemotherapeutic medications include CVD (cyclophosphamide/vincristine/dacarbazine) or temozolomide-based regimen. I131 MIBG therapy can be considered in patients requiring systemic treatment and who have MIBG-avid disease [30].

Epidemiology, Presentation, and Pathogenesis
Urinary bladder NENs are classified into well-differentiated NENs, small-cell NENs, large-cell NENs, and paragangliomas (Table 5) [28]. They comprise <1% of the urinary bladder tumors and are more common in males with a male-to-female ratio of 3.3:1.0 [64,65]. A small-cell variant is the common NEN of the urinary bladder, with an estimated 500 cases per year [64]. It constitutes 0.3-0.7% of primary bladder malignancies [66]. Small-cell NEC of the urinary bladder was first described by Cramer et al. in 1981 [66]. Note that 88% of small-cell NEC patients presented with hematuria in a study by Cheng et al. [65]. Around 60% of patients are diagnosed with metastatic disease at diagnosis [67].  Urinary bladder NENs are classified into well-differentiated NENs, small-cell NENs, large-cell NENs, and paragangliomas (Table 5) [28]. They comprise <1% of the urinary bladder tumors and are more common in males with a male-to-female ratio of 3.3:1.0 [64,65]. A small-cell variant is the common NENs of the urinary bladder, with an estimated 500 cases per year [64]. It constitutes 0.3-0.7% of primary bladder malignancies [66]. Small-cell NEC of the urinary bladder was first described by Cramer et al. in 1981 [66]. Note that 88% of small-cell NEC patients presented with hematuria in a study by Cheng et al. [65]. Around 60% of patients are diagnosed with metastatic disease at diagnosis [67]. Cigarette smoking is a risk factor in 50-70% of small-cell bladder NECs [68]. Additionally, small-cell NEC is predominant in the sixth to seventh decades of life. In contrast, well-differentiated NENs of the urinary bladder are rare and are usually seen in middle-aged individuals; there is a slight predominance in males [69,70]. Large-cell NEC constitutes <0.5% of all the bladder urothelial carcinomas and is usually reported in male (77.1% vs. 23%), elderly patients (>60 years) [24,71,72]. In the urinary tract, the bladder is the most common site for the origin of large-cell NEC [73,74]. The urinary bladder (79.2%), followed by urethra (13%), pelvis (5%), and ureter (3%) are the most common sites of paraganglioma in the genitourinary tract [75,76]. The first case of urinary bladder paraganglioma was reported in 1953 by Zimmerman et al. [77]. Bladder paragangliomas account for 0.05-0.1% of all bladder tumors and 6% of paragangliomas [78,79]. Females are three times more commonly affected than males [80]. Functional paragangliomas secrete catecholamines resulting in hypertension, diaphoresis, headache, palpitations, and post-micturition syncope [81]. The characteristic triad of paroxysmal or sustained hypertension, gross hematuria, and micturition syncope can be observed in >75% of patients [46,82].
Well-differentiated NENs are derived from the neuroendocrine cells in the normal urothelial and reactive urothelial basement membrane. There are three proposed theories to explain the cells of origin of small-cell urinary bladder NENs: (i) From undifferentiated and multipotent cells or stem cells in the urothelium. This theory supports the frequent co-existence of small-cell NEC and urothelial carcinoma. (ii) From neuroendocrine cells of the regular or metastatic urothelium and (iii) from undefined submucosal neuroendocrine cells [83]. While 10-30% of patients present with a pure form of small-cell NEC, around 70-90% of patients, small-cell carcinoma coexists with adenocarcinoma, squamous cell carcinoma, or urothelial carcinoma [65,84]. Large-cell NEC of the urinary bladder can occur as a pure variant or associated with squamous cell carcinoma, carcinosarcoma, primary adenocarcinoma of the bladder, or urothelial carcinoma [85]. Pheochromocytomas at the extra-adrenal sites are termed paragangliomas. They arise from the sympathetic chain in the detrusor muscle and may occur anywhere in the urinary bladder [46,82]. Although most of the cases are sporadic, a few cases of bladder paraganglioma are associated with hereditary syndromes, such as neurofibromatosis, Sturge-Weber syndrome, von Hippel-Lindau syndrome, tuberous sclerosis, and the Carney triad (pulmonary chondromas, paragangliomas, and gastrointestinal stromal tumors) [86].

Imaging
Well-differentiated NENs of the urinary bladder appear as polyps or submucosal nodules with occasional inflammatory changes in cystoscopy (Figure 8) [69]. Most of the tumors are small, ranging from 2 to 10 mm, and involve neck and trigone regions of the bladder [69]. The CT and MR imaging of a small-cell NEC of the urinary bladder shows a broad-based polypoid mass with or without necrotic and cystic areas (Figures 9 and 10). The mass displays patchy enhancement with contrast administration and exhibits invasion of the entire thickness of the bladder wall at the time of diagnosis. Bladder wall invasion is typical in tumors ranging from 3 to 8 cm in size. Kim et al. reported that the small-cell NEC of the urinary bladder is hypointense on both T1 and T2-weighted MR imaging due to the high tumor cellularity [87]. The aggressiveness of small-cell NEC of the urinary bladder is reflected in its adjacent structural invasion of the vagina, uterus, ureters, peritoneum, and abdominal muscles. Lymph node involvement can be noticed in 66% of the patients with distant metastases in the lung, liver, and bone [86,87].
Paraganglioma appears as a sub-mucosal homogeneous or heterogeneous hyperenhancing lobulated mass on contrast-enhanced CT. A ring-like peripheral calcification is highly suggestive of a paraganglioma [88]. MR imaging is superior to CT and demonstrates low-signal intensity on T1 and moderately high signal intensity on T2-weighted imaging sequences [86]. Multiple signal voids with hyperintense foci can be seen on MR imaging, resulting in a "salt-and-pepper appearance" [78]. The enlarged feeding arteries and intense tumor blush are observed on angiography. Iodine-131 metaiodobenzylguanidine (MIBG) scan has higher specificity (96%) than CT or MRI to detect paraganglioma and aids in evaluating metastatic disease [86]. At the same time, MR imaging (88%) is more sensitive than CT (64%) or iodine-131 MIBG (64%) when identifying the extra-adrenal paragangliomas [89]. Metastatic lymph nodes are visualized by PET scan with 6-[18F] fluorodopamine scan, which is superior to iodine-131 MIBG [90]. Most of the tumors are benign, whereas 10-15% of tumors exhibit malignant behavior [91].
Immunohistochemistry reveals positivity for synaptophysin, chromogranin A, and cytokeratin AE1-AE3 [92]. Diagnosis of small-cell NEC of the urinary bladder is based on WHO diagnostic criteria for small-cell lung carcinoma, which include morphological characteristics (Table 5) [93]. Small-cell NEC of the urinary bladder stain positive for chromogranin, CD57 CD56, synaptophysin, TTF-1, neuron-specific enolase, CAM5.2, keratin7, and the epithelial membrane antigen GATA3 in immunohistochemical analysis. A dot-like reactivity to CAM5.2 can also be noticed. Synaptophysin (64.3%) and CD56 (71%) have higher sensitivity than chromogranin A (29%) in the tumor differentiation [94]. Up to 33-39% of small-cell NECs of urinary bladder demonstrate positive staining for TTF1 [95,96]. The paraganglioma appears as a well-circumscribed nodule on gross examination and shows cells arranged in the Zellballen pattern on microscopic examination (Table 5) [97]. Immunohistochemistry of the tumor reveals positive synaptophysin and chromogranin staining in chief cells, and positive S-100 and negative cytokeratin staining in sustentacular cells. Negative cytokeratin differentiates paragangliomas from urothelial and carcinoid tumors, which usually stain positive for cytokeratin [78]. Paragangliomas with succinate dehydrogenase B mutations are likely to exhibit malignant behavior [28].
Cancers 2022, 14, x FOR PEER REVIEW 11 of 2 entire thickness of the bladder wall at the time of diagnosis. Bladder wall invasion is typ ical in tumors ranging from 3 to 8 cm in size. Kim et al. reported that the small-cell NEC of the urinary bladder is hypointense on both T1 and T2-weighted MR imaging due to th high tumor cellularity [87]. The aggressiveness of small-cell NEC of the urinary bladde is reflected in its adjacent structural invasion of the vagina, uterus, ureters, peritoneum and abdominal muscles. Lymph node involvement can be noticed in 66% of the patient with distant metastases in the lung, liver, and bone [86,87].   entire thickness of the bladder wall at the time of diagnosis. Bladder wall invasion is typical in tumors ranging from 3 to 8 cm in size. Kim et al. reported that the small-cell NEC of the urinary bladder is hypointense on both T1 and T2-weighted MR imaging due to the high tumor cellularity [87]. The aggressiveness of small-cell NEC of the urinary bladder is reflected in its adjacent structural invasion of the vagina, uterus, ureters, peritoneum, and abdominal muscles. Lymph node involvement can be noticed in 66% of the patients with distant metastases in the lung, liver, and bone [86,87].   Paraganglioma appears as a sub-mucosal homogeneous or heterogeneous hyper-e hancing lobulated mass on contrast-enhanced CT. A ring-like peripheral calcification highly suggestive of a paraganglioma [88]. MR imaging is superior to CT and demo strates low-signal intensity on T1 and moderately high signal intensity on T2-weight imaging sequences [86]. Multiple signal voids with hyperintense foci can be seen on M imaging, resulting in a "salt-and-pepper appearance" [78]. The enlarged feeding arter and intense tumor blush are observed on angiography. Iodine-131 metaiodobenzylgua idine (MIBG) scan has higher specificity (96%) than CT or MRI to detect paragangliom and aids in evaluating metastatic disease [86]. At the same time, MR imaging (88%) more sensitive than CT (64%) or iodine-131 MIBG (64%) when identifying the extra-a renal paragangliomas [89]. Metastatic lymph nodes are visualized by PET scan with [18F] fluorodopamine scan, which is superior to iodine-131 MIBG [90]. Most of the tumo are benign, whereas 10-15% of tumors exhibit malignant behavior [91].
Immunohistochemistry reveals positivity for synaptophysin, chromogranin A, a cytokeratin AE1-AE3 [92]. Diagnosis of small-cell NEC of the urinary bladder is based WHO diagnostic criteria for small-cell lung carcinoma, which include morphologic characteristics (Table 5) [93]. Small-cell NEC of the urinary bladder stain positive for chr mogranin, CD57 CD56, synaptophysin, TTF-1, neuron-specific enolase, CAM5.2, keratin and the epithelial membrane antigen GATA3 in immunohistochemical analysis. A do like reactivity to CAM5.2 can also be noticed. Synaptophysin (64.3%) and CD56 (71 have higher sensitivity than chromogranin A (29%) in the tumor differentiation [94]. U to 33-39% of small-cell NECs of urinary bladder demonstrate positive staining for TT [95,96]. The paraganglioma appears as a well-circumscribed nodule on gross examinati and shows cells arranged in the Zellballen pattern on microscopic examination (Table [97]. Immunohistochemistry of the tumor reveals positive synaptophysin and chr mogranin staining in chief cells, and positive S-100 and negative cytokeratin staining sustentacular cells. Negative cytokeratin differentiates paragangliomas from urothel and carcinoid tumors, which usually stain positive for cytokeratin [78]. Paragangliom with succinate dehydrogenase B mutations are likely to exhibit malignant behavior [28

Prognosis and Management
The pure form of well-differentiated NEN of the urinary bladder is associated wi good outcomes. Most of the tumors are so small that they can be wholly resected duri a biopsy. Nonetheless, 25% of patients exhibit distant or regional lymph nodal metastas [82]. The stage is the most important prognostic factor in small-cell NEC. Five-year su vival rates range from 8 to 16% in low-high stage disease ( Figure 11) [65,92,98]. Patien with large-cell NEC present at late stages and have a median survival of 20-23 mont [68]. The presence of features such as hypertension micturition attacks, presentation a younger age, and invasion through the bladder wall, indicates a high potential for mal nant progression [82]. The differentiation solely based on gross or histologic

Prognosis and Management
The pure form of well-differentiated NENs of the urinary bladder is associated with good outcomes. Most of the tumors are so small that they can be wholly resected during a biopsy. Nonetheless, 25% of patients exhibit distant or regional lymph nodal metastases [82]. The stage is the most important prognostic factor in small-cell NEC. Five-year survival rates range from 8 to 16% in low-high stage disease ( Figure 11) [65,92,98]. Patients with large-cell NEC present at late stages and have a median survival of 20-23 months [68]. The presence of features such as hypertension micturition attacks, presentation at a younger age, and invasion through the bladder wall, indicates a high potential for malignant progression [82]. The differentiation solely based on gross or histological characteristics is challenging; however, the deep tissue invasion, lymph node involvement, and distant metastases indicate the malignant activity of the tumor [97]. The staging of the urinary bladder malignancies is described in Table 6 and Figure 11. Chemotherapy with/without radiation is the preferred treatment, alongside surgery, in small-cell NEC of the urinary bladder. The standard treatment of bladder paragangliomas is surgical resection with appropriate pre-and post-operative adrenergic blockade to prevent a hypertensive crisis ( Figure 12). The tumor can be contracted through transurethral or open/laparoscopic radical or partial cystectomy in conjunction with lymph node dissection [78,99]. Adjuvant radiation therapy can provide better survival for individuals enduring malignant tumors [79]. Table 6. AJCC staging of urinary bladder malignancy-8th edition [100,101]. N2-Multiple regional lymph node involvement; N3-Common iliac lymph node in-volvement IVA T4b Any N M0 T4b-Tumor invasion into pelvic or abdominal wall Any T Any N M1a

Stage TNM Category Description
M1a-Distant metastases to lymph nodes beyond common iliac arteries IVB Any T Any N M1b M1b-Distant metastases to sites such as bones, liver or lungs

Epidemiology, Presentation, and Pathogenesis
Primary ureteral NENs are rare, and no more than 50 cases of small-cell ureteral NEC have been reported in the literature [2,102]. Small-cell NEC of the ureter is usually observed in elderly patients, and around 15 cases have been observed in females so far [2,102,103]. As per our knowledge, less than 10 cases of large-cell NEC of the ureter [73,74] have been reported in the literature. Neuroendocrine cells are not usually found in the urinary tract. The pathogenesis of ureteral NENs is still disputed and hypothesized to be similar to that of bladder NENs [104,105]. Most of the NENs arise from the lower ureteral segment. Collision tumors are rare, in which tumors of two or more types coexist in the same organ and do not intermix. Approximately 50% of ureteral small-cell NECs account for collision tumors [106,107]. Around 62% of patients demonstrate small-cell NEC associated with urothelial carcinoma [108].
Clinical presentation is varied, ranging from asymptomatic to complete ureteral obstruction resulting in hydronephrosis [109]. In contrast to bladder masses obstructing bilateral ureters, ureteral NENs is unilateral and does not usually cause oligo-anuria in bi-nephric individuals. Gross hematuria and flank pain are the most common symptoms of small-cell ureteral NEC. Endoscopy provides the biopsy specimen, which aids in diagnosing the mass by revealing malignant neuroendocrine cells [74,110]. A few may also present with paraneoplastic syndromes, which indicate advanced or extensive disease [102]. Ouzzane et al. reported that 72% of patients presented with pT3 or pT4 stages, and 54% developed metastases within 13 months [108].

Imaging
Screening of ureteral NENs is challenging due to non-specific symptoms, such as ureteral obstruction or hematuria. As the most common presentation includes hematuria and hydronephrosis, ultrasonography (USG) is the initial investigation of choice to exclude urinary tract stones. USG, although it detects ureteral distention, is insensitive to ureteral tumors. Retrograde urography can detect the luminal mass indirectly by showing a filling defect in the ureteral lumen [109]. Finally, grossly, ureteral NENs are solid and sessile; they have gray to white cut surfaces, firm consistency, and peritumoral mural thickening ( Figure 13) [74,110]. Microscopically, the tumor has a desmoplastic stromal reaction, a high ki-67 index (>50-60%), necrosis, adjacent structural invasion, and lymphovascular invasion, in addition to specific cellular characteristics described in the other sections ( Figure 13) [74,[110][111][112].
Histologic examination of small-cell NEC of the ureter may reveal small palisading cells with scant to moderate cytoplasm, high nuclear-cytoplasmic ratios, finely speckled chromatin, and high mitotic counts ( Table 7). The specimen stains positive for CAM5.2, chromogranin A, synaptophysin, neuron-specific enolase, pan-cytokeratin (AE1/AE3), and CD56 ( Figure 13). Around 44% of extrapulmonary small-cell cancers stain positive for thyroid-transcription factor-1 [113,114]. Although ureteral metastases are rare, it is prudent to exclude metastatic small-cell NEC to the upper urinary tract during the diagnosis [103,115,116].
The diagnostic criteria for large-cell NEC of the ureter are based on the pulmonary counterpart: (i) Morphological characteristics of a neuroendocrine tumor (palisading, organoid nesting, trabeculae, or rosettes). (ii) High mitotic activity (>11/HPF with a median of 70/HPF). (iii) Large necrotic zone. (iv) Microscopic cellular characteristics of a non-small-cell carcinoma (large cells with low nuclear-cytoplasmic ratio, vesicular/fine/coarse chromatin, and frequent nucleoli). (v) Positive immunohistochemistry for ≥1 neuroendocrine marker (except neuron-specific enolase) and neuroendocrine granules (100-200 nm membrane-bound cytoplasmic granules) [74]. The differential diagnosis of large-cell ureteral NEC and its distinguishing features are described in Table 8. urinary tract stones. USG, although it detects ureteral distention, is insensitive to ureteral tumors. Retrograde urography can detect the luminal mass indirectly by showing a filling defect in the ureteral lumen [109]. Finally, grossly, ureteral NENs are solid and sessile; they have gray to white cut surfaces, firm consistency, and peritumoral mural thickening ( Figure 13) [74,110]. Microscopically, the tumor has a desmoplastic stromal reaction, a high ki-67 index (>50-60%), necrosis, adjacent structural invasion, and lymphovascular invasion, in addition to specific cellular characteristics described in the other sections (Figure 13) [74,[110][111][112]. Histologic examination of small-cell NEC of the ureter may reveal small palisading cells with scant to moderate cytoplasm, high nuclear-cytoplasmic ratios, finely speckled chromatin, and high mitotic counts ( Table 7). The specimen stains positive for CAM5.2, chromogranin A, synaptophysin, neuron-specific enolase, pan-cytokeratin (AE1/AE3), and CD56 ( Figure 13). Around 44% of extrapulmonary small-cell cancers stain positive for thyroid-transcription factor-1 [113,114]. Although ureteral metastases are rare, it is prudent to exclude metastatic small-cell NEC to the upper urinary tract during the diagnosis [103,115,116].

Prognosis and Management
Ureteral NENs are aggressive, among which small-cell NEC has a rapid progression and dismal prognosis with a median overall survival of 17 months [113,117]. Most of the patients present with locally advanced disease, and 20% have had lymph node involvement at diagnosis [109]. The small-cell ureteral NEC's 1-and 3-year overall survival rates are 52% and 30%, respectively [106]. The pathologic stage is the most important prognostic factor. The median survival times of patients with stages pT1-pT2 and pT3-pT4 are around 31 and 8 months, respectively [113]. Zhong et al. reported regional recurrences and distant metastasis in 9.4% and 25% of patients with early-stage disease, respectively, during a short follow-up [106]. Vimentin positive small-cell ureteral NEC had a poor prognosis in a study by Chuang et al.; however, further studies are required to determine the efficacy of vimentin in predicting the prognosis [1].
There are no well-established strategies for treating small-cell ureteral NEC due to limited data, and hence, decision-making depends on small-cell lung carcinoma treatment strategies. Oncologists consider a multimodality approach with surgery, adjuvant chemotherapy, and radiation ( Figure 14) [118]. The staging of ureteral cancers is described in Table 9 and Figure 15. Radical resection is preferred in early-stage, small-cell ureteral NEC ( Figure 14). However, if the patient has upper urinary tract urothelial carcinoma, nephroureterectomy with bladder cuff excision is recommended. The median survival ranges from 8.2 months with surgery alone to 24 months with adjuvant platinum-based chemotherapy [111,113,114]. Platinum-based chemotherapy with EP (etoposide and cisplatin) or CE (carboplatin and etoposide) has shown a response rate of 69% [119]. The irinotecan and cisplatin have also been shown to achieve the tumor reduction [111,120]. Studies show that adjuvant chemotherapy has more favorable outcomes compared to surgery alone. The median overall survival times for patients who received adjuvant chemotherapy and surgery alone were 24 and 12 months, respectively (p = 0.56) [108,113]. The efficacy of immunotherapy has not been studied in the case of small-cell ureteral NEC. Immunotherapies targeting EGFR, BCL-2, C-kit, CD56, and PDGFR-α might be promising approaches [103,121,122].

R REVIEW
17 of 25 prognosis in a study by Chuang et al.; however, further studies are required to determine the efficacy of vimentin in predicting the prognosis [1]. There are no well-established strategies for treating small-cell ureteral NEC due to limited data, and hence, decision-making depends on small-cell lung carcinoma treatment strategies. Oncologists consider a multimodality approach with surgery, adjuvant chemotherapy, and radiation ( Figure 14) [118]. The staging of ureteral cancers is described in Table 9 and Figure 15. Radical resection is preferred in early-stage, small-cell ureteral NEC ( Figure 14). However, if the patient has upper urinary tract urothelial carcinoma, nephroureterectomy with bladder cuff excision is recommended. The median survival ranges from 8.2 months with surgery alone to 24 months with adjuvant platinum-based chemotherapy [111,113,114]. Platinum-based chemotherapy with EP (etoposide and cisplatin) or CE (carboplatin and etoposide) has shown a response rate of 69% [119]. The irinotecan and cisplatin have also been shown to achieve the tumor reduction [111,120]. Studies show that adjuvant chemotherapy has more favorable outcomes compared to surgery alone. The median overall survival times for patients who received adjuvant chemotherapy and surgery alone were 24 and 12 months, respectively (p = 0.56) [108,113]. The efficacy of immunotherapy has not been studied in the case of small-cell ureteral NEC. Immunotherapies targeting EGFR, BCL-2, C-kit, CD56, and PDGFR-α might be promising approaches [103,121,122].  Table 9. TNM staging of ureteral malignancies [123].

M Staging
Description a N0 M0 Non-invasive papillary tumor

Urethral NEN
Squamous cell carcinoma is the most common urethral malignancy constituting 50-70% of cases, followed by transitional cell carcinoma and adenocarcinoma [124]. Neuroendocrine neoplasms of the urethra are rare. Most of the cases reported in the literature were mixed variants containing elements of the transitional cell, squamous cell, and adenocarcinoma. Such presentation implies the derivation of NEN from primitive precursor cells or metastatic epithelium [125].
Small-cell urethral NEC expresses both neural and epithelial markers. Neuron-specific enolase (89%), synaptophysin (50%), and chromogranin (50%) are the neural markers; and epithelial membrane antigen (56%) and carcinoembryonic antigen (57%) are the epithelial markers that can be observed in small-cell urethral NEC. Synaptophysin and chromogranin are highly specific, whereas the rest of the neural and epithelial marks exhibit poor specificity [126]. The differential diagnoses of urethral NEC are described in Table 10. Early clinical diagnosis, staging (Table 11 and Figure 16), and pathological diagnosis are imperative to improve the malignancy outcome. Aggressive treatment with surgery and adjuvant chemotherapy is recommended in limited small-cell NEC of the urethra. In the case of unresectable carcinoma, systemic chemotherapy might be considered. Studies show that cisplatin-based chemotherapy significantly predicts improved survival [127].

Differential Diagnosis
Characteristic of Urethral NEN That Helps in Distinguishment

Urethral NENs
Squamous cell carcinoma is the most common urethral malignancy constituting 50-70% of cases, followed by transitional cell carcinoma and adenocarcinoma [124]. Neuroendocrine neoplasms of the urethra are rare. Most of the cases reported in the literature were mixed variants containing elements of the transitional cell, squamous cell, and adenocarcinoma. Such presentation implies the derivation of NENs from primitive precursor cells or metastatic epithelium [125].
Small-cell urethral NEC expresses both neural and epithelial markers. Neuron-specific enolase (89%), synaptophysin (50%), and chromogranin (50%) are the neural markers; and epithelial membrane antigen (56%) and carcinoembryonic antigen (57%) are the epithelial markers that can be observed in small-cell urethral NEC. Synaptophysin and chromogranin are highly specific, whereas the rest of the neural and epithelial marks exhibit poor specificity [126]. The differential diagnoses of urethral NEC are described in Table 10. Early clinical diagnosis, staging (Table 11 and Figure 16), and pathological diagnosis are imperative to improve the malignancy outcome. Aggressive treatment with surgery and adjuvant chemotherapy is recommended in limited small-cell NEC of the urethra. In the case of unresectable carcinoma, systemic chemotherapy might be considered. Studies show that cisplatin-based chemotherapy significantly predicts improved survival [127]. Table 10. Differential diagnosis of small-cell urethral NEC [124,125,128].

Lymphoma
Positive immunohistochemistry with LCA antigen Transitional cell carcinoma Positive p63 and CD44v6 (80% specific) Carcinoid tumor Abundant eosinophilic cytoplasm and regular nuclei Primary neuroectodermal tumor Larger cell bodies with spread out cytoplasm in dendritic processes Metastatic small-cell carcinoma Positive TTF-1 and presence of primary site on chest CT Merkel cell carcinoma Penile or scrotal skin involvement and presence of punctate paranuclear cytokeratin staining; positive CK20 Table 11. AJCC staging of urethral malignancies [129].

Conclusions
This study represents a comprehensive review of the primary urinary tract NENs. Among NENs, those arising in the urinary tract are rare and aggressive. They require multimodal treatment in most cases. The tumor diagnosis is challenging despite the imaging, molecular, and biochemical advancements. Continued research and more extensive studies are needed to determine the biological behavior and effective management of these rare tumors.